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# Purpose of Review Chronic pain continues to be one of the leading healthcare cost burdens in the United States and is typically defined as ongoing pain, lasting longer than six months. Various treatment options exist for chronic pain, including physical therapy, medical management, pain psychology, and interventional therapies. Pain medications have been the mainstay of treatment for chronic pain conditions with an increasing use of membrane stabilizers and antidepressants to treat neuropathic pain conditions. Specifically, serotonin noradrenaline reuptake inhibitors (SNRIs) have been used to treat a range of pain conditions expanding from everyday use for depressive disorders. # Recent Findings SNRIs, including duloxetine, venlafaxine, and milnacipran, have demonstrated efficacy in reducing pain in musculoskeletal pain (chronic low back pain and osteoarthritis), fibromyalgia, and neuropathic pain conditions (peripheral diabetic neuropathy). # Summary The article describes the function, role, and use of SNRIs to treat chronic and neuropathic pain by altering the noradrenergic descending inhibitory pathways.

Narcolepsy is a debilitating sleep disorder that presents with excessive daytime sleepiness (EDS) and cataplexy, which is a sudden paralysis of muscle tone triggered by strong emotions such as laughing. It is also associated with many other disorders, including psychiatric disorders, neurologic illnesses, and medication side effects. Common causes of delayed and incorrect diagnoses of these conditions include lack of physician familiarity with narcolepsy symptoms and comorbidities which mask narcolepsy signs and symptoms. Current pharmacologic therapies include Modafinil and Armodafinil for EDS and sodium oxybate for cataplexy. This review discusses the epidemiology, pathophysiology, risk factors, presentation, treatment of narcolepsy, and the role of a novel drug, Pitolisant, in the treatment of EDS in adults with narcolepsy. Pitolisant is a histamine-3 receptor (H3R), competitive antagonist, and inverse agonist, acting through the histamine system to regulate wakefulness. It is a novel drug approved in August 2019 by the FDA, is not classified as a controlled substance, and is approved for use in Europe and the United States to treat EDS and cataplexy in narcolepsy. Recent phase II and III trials have shown that Pitolisant helps reduce the ESS score and cataplexy. In summary, based on comparative studies, recent evidence has shown that Pitolisant is non-inferior to Modafinil in the treatment of EDS but superior to Modafinil in reducing cataplexy.

Post-traumatic stress disorder (PTSD) is a psychiatric disorder that causes significant functional impairment and is related to altered stress response and reinforced learned fear behavior. PTSD has been found to impact three functional networks in the brain: default mode, executive control, and salience. The executive control network includes the dorsolateral prefrontal cortex (DLPFC) and lateral PPC. The salience network involves the anterior cingulate cortex, anterior insula, and amygdala. This latter network has been found to have increased functional connectivity in PTSD. Transcranial Magnetic Stimulation (TMS) is a technique used in treating PTSD and involves stimulating specific portions of the brain through electromagnetic induction. Currently, high-frequency TMS applied to the left dorsolateral prefrontal cortex (DLPFC) is approved for use in treating major depressive disorder (MDD) in patients who have failed at least one medication trial. In current studies, high-frequency stimulation has been shown to be more effective in PTSD rating scales posttreatment than low-frequency stimulation. The most common side effect is headache and scalp pain treated by mild analgesics. Seizures are a rare side effect and are usually due to predisposing factors. Studies have been done to assess the overall efficacy of TMS. However, results have been conflicting, and sample sizes were small. More research should be done with larger sample sizes to test the efficacy of TMS in the treatment of PTSD. Overall, TMS is a relatively safe treatment. Currently, the only FDA- approved to treat refractory depression, but with the potential to treat many other conditions.

Schizophrenia is a debilitating psychotic disorder characterized by positive symptoms such as delusions, hallucinations, and disorganized thoughts, and negative symptoms like lack of effect or motivation. Bipolar 1 disorder (B1D) is a psychiatric illness characterized by recurrent manic episodes in alternation with depressive episodes and interspersed periods of euthymia, ultimately resulting in psychological distress and impairment of daily functioning. Effective treatments are needed for both schizophrenia and B1D to reach the treatment goals of reducing the debilitating symptomology, improving social functioning and quality of life, and increasing the chances of recovery and more favorable long-term outcomes. To date, olanzapine is one of the most efficacious atypical antipsychotics (AAPs) for the treatment of both schizophrenia and B1D and is associated with fewer extrapyramidal effects compared to other treatments. However, compared to other AAPs, olanzapine is associated with a greater chance of metabolic syndrome, limiting its clinical use and affecting treatment compliance. Samidorphan mitigates the weight gain side effects of olanzapine by antagonizing μ-, κ-, and δ-opioid receptors. The use of combination drugs to treat psychiatric conditions is an emerging field with the goal of increasing therapeutic efficacy and decreasing undesirable side effects. Clinical trials have demonstrated combination on olanzapine and samidorphan (OLZ/SAM) treatment resulted in significantly less weight gain than olanzapine monotherapy. Clinical trial patients reported improvements in symptoms of psychosis, reduced weight gain, and overall satisfaction with their treatment. OLZ/SAM has been as shown to be a safe and effective pharmaceutical option for the clinical management of schizophrenia and B1D.

A migraine is a clinical diagnosis with a presentation of one or more severe unilateral or bilateral headache(s) often preceded by an aura and typically accompanied by nausea, vomiting, photophobia, and/or phonophobia. This neurological disease is often debilitating and greatly affects the quality of life of those it inflicts. In fact, a recent study conducted by the Global Burden of Disease and published in The Lancet Neurology revealed that migraines ranked second to only back pain as the most disabling disease. Triggers for migraines have ranged from female sex, low socioeconomic status, and diet to loud noises, sleep hygiene, and stress. Along with its clinical presentation, laboratory tests and imaging help rule out other potential causes of the headache and lead to a diagnosis of migraine. Migraines are typically divided into three phases: prodromal, headache, and postdrome. The pathophysiology of each phase remains under investigation, with differing theories regarding their pathways. Existing therapies are abortive therapies for acute migraines or preventative therapies. Abortive therapy consists of NSAIDs and triptans. Preventative therapies include tricyclic antidepressants, calcium channel blockers, beta-blockers, and anticonvulsants. In this review, we focus on the role of NSAIDs and the COX-2 inhibitor, celecoxib oral solution, for the abortive treatment of acute migraines.

Parkinson’s disease (PD) is a common neurodegenerative disorder that leads to significant morbidity and disability. PD is caused by a loss of dopaminergic, cholinergic, serotonergic, and noradrenergic neurons in the central nervous system (CNS), and peripherally; the syndromic parkinsonism symptoms of movement disorder, gait disorder, rigidity and tremor are mostly driven by the loss of these neurons in the basal ganglia. Unfortunately, a significant proportion of patients taking levodopa, the standard of care treatment for PD, will begin to experience a decrease in effectiveness at varying times. These periods, referred to as “off episodes”, are characterized by increased symptoms and have a detrimental effect on quality of life and disability. Istradefylline, a novel adenosine A2A receptor antagonist, is indicated as a treatment addition to levodopa/carbidopa in patients experiencing “off episodes”. It promotes dopaminergic activity by antagonizing adenosine in the basal ganglia. This review will discuss istradefylline as a treatment for PD patients with off episodes.

Multiple sclerosis (MS) is a prevalent and debilitating neurologic condition characterized by widespread neurodegeneration and the formation of focal demyelinating plaques in the central nervous system. Current therapeutic options are complex and attempt to manage acute relapse, modify disease, and manage symptoms. Such therapies often prove insufficient alone and highlight the need for more targeted MS treatments with reduced systemic side effect profiles. Ozanimod is a novel S1P (sphingosine-1-phosphate) receptor modulator used for the treatment of clinically isolated syndrome, relapsing–remitting, and secondary progressive forms of multiple sclerosis. It selectively modulates S1P1 and S1P5 receptors to prevent autoreactive lymphocytes from entering the CNS where they can promote nerve damage and inflammation. Ozanimod was approved by the US Food and Drug Administration (US FDA) for the management of multiple sclerosis in March 2020 and has been proved to be both effective and well tolerated. Of note, ozanimod is associated with the following complications: increased risk of infections, liver injury, fetal risk, increased blood pressure, respiratory effects, macular edema, and posterior reversible encephalopathy syndrome, among others. Further investigation including head-to-head clinical trials is warranted to evaluate the efficacy of ozanimod compared with other S1P1 receptor modulators.

Abstract Acupuncture is a form of traditional Chinese medicine that is performed by placing needles or pressure in specific locations on a patient’s skin to achieve a therapeutic effect. Although used to treat a variety of disorders, one of the most common applications of acupuncture is to treat chronic pain, especially headache and migraine pain. Migraines are difficult to treat, and pharmacotherapies are often the first line of treatment, although these options have many unwanted side effects, such as exacerbation of headache pain in those with chronic migraine. Many complimentary and integrative therapies are available to treat migraine (including nutraceuticals, yoga, tai chi, and biofeedback), among which acupuncture as a treatment is gaining increasing attention. In this review, we provide an overview of the current understanding of both acupuncture and migraine and of current research investigating the effectiveness of acupuncture in treating migraine and chronic migraine.

Abstract Purpose of Review This is a comprehensive review of the current literature on the usage of galcanezumab for migraine treatment. It reviews the biology, pathophysiology, epidemiology, diagnosis, and conventional treatment of migraines, then compares the literature available for galcanezumab with historical treatment options. Recent Findings Migraine is a common headache disorder and constitutes a significant source of distress from both a personal and societal perspective. Conventional treatment includes abortive and preventive treatment. Treatment options are limited and may be only partially or minimally effective in some of the population. Recent evidence points to metabolic changes in the brain as possible causes of migraine, via reduced available energy or a spiking need for it, resulting in a relative insufficiency. This leads to trigeminocervical complex (TCC) activation and a headache episode, modulated by calcitonin gene-related peptide (CGRP). Galcanezumab (Emgality) is a monoclonal antibody targeting CGRP that is given in a monthly injection for the prevention of migraines. Its safety was previously shown in phase 1 and 2 trials, and recent phase 3 trials showed efficacy, with up to 50% reduction in monthly migraine days and improved functional capacity in migraineurs. Studies show that the drug is well tolerated and safe. Summary Migraine headache is a common neurological syndrome that causes great pain and suffering. Treatment options today are limited. Galcanezumab does not prevent migraines, but it is effective in decreasing their frequency and length. It is also much better tolerated than the currently existing therapies. While it is unlikely to provide monotherapy for migraines, it is a novel therapy that may be added for cases of severe or frequent migraines.

Abstract It is estimated that one-third of oncologic patients in the USA do not receive analgesia proportional to or adequate for the intensity of their pain. A mechanism-based approach to oncologic pain therapy is critical to ensure that analgesia regimens are individualized and effective. Since the mechanisms that lead to cancer pain are complex, healthcare providers must be willing to elicit and recognize the symptoms of each individual patient since these factors influence both the experience of pain and response to treatment. This process is centered on the use of detailed history in order to understand symptom expression in the context of primary tumor diagnosis and progression, history of cancer pain, psychological distress, sleep disturbances, cognitive function, and addictive behavior. Incorporating all of these factors into the assessment of a patient’s pain condition can facilitate management decisions and help predict patient response to treatment.

Abstract Hereditary variant transthyretin amyloidosis (ATTRv) is a rare genetic defect that affects about 5000–10,000 people worldwide, causing amyloidosis secondary to misfolding of mutant transthyretin (TTR) protein fibrils. TTR mutations can cause protein deposits in many extracellular regions of organs, but those deposits in cardiac and axonal cells are the primary cause of this clinical syndrome. Treatment options are limited, but new drugs are being developed. Patisiran, a novel drug, is a liposomal siRNA against TTR that specifically targets this protein, reducing the accumulation of TTR in tissues, with subsequent improvement in both neuropathy and cardiac function. Patisiran is likely to serve as a prototype for the development of further intelligent drug solutions for use in targeted therapy. In this review we summarize the evidence currently available on the treatment of polyneuropathy in people with ATTRv with patisiran. We review the evidence on its efficacy, safety, and indications of use, citing novel and seminal papers on these subjects.

Abstract Introduction Recent years have seen a dramatic escalation of off-label prescribing for gabapentin and pregabalin (gabapentinoids) owing in part to generic versions of each being released over the past two decades, but also in part as a response to increasing calls for multimodal and non-opioid pain management strategies. In this context, several recent articles have been published alleging widespread misuse, with speculations on the unappreciated addictive potential of the gabapentinoid class of drugs. Reports of a 1% population-level abuse prevalence stem from a single internet survey in the UK, and the vanishingly small adverse event outcomes data do not support such frequency. In this targeted narrative review, we aim to disabuse pain physicians and other clinicians, pharmacists, and policymakers of both the positive and negative myths concerning gabapentinoid medications. Results Gabapentinoids inhibit the joint action of voltage-gated calcium channel (VGCC) α2δ subunits in conjunction with the n-methyl-d-aspartate (NMDA) receptor, with subsequent downregulation of VGCC expression and excitatory neurotransmitter release, and possibly synaptogenesis as well, through actions on thrombospondins. These activities reduce the likelihood of central sensitization, which explains in part the efficacy of the gabapentinoids in the management of neuropathic pain. Gabapentinoids also facilitate slow-wave sleep, a relatively rare phenomenon among central nerve system-acting agents, which is also thought to explain some of the therapeutic benefit of the class in conditions such as fibromyalgia. The number needed to treat to see benefit overlaps that of the nonsteroidal anti-inflammatory drugs, but with a considerably improved safety profile. Along these lines, in the context of over 50 million prescriptions per year in the USA alone, the gabapentinoids display remarkably low risk, including risks of misuse, abuse, and dependence. Furthermore, the neurobiology of these agents does not lend plausibility to the allegations, as they have never been shown to elicit dopaminergic activity within the nucleus accumbens, and in addition likely confer a "negative-feedback loop" for habituation and dependence by serving as functional NMDA antagonists, possibly through their actions on thrombospondins. Clinical and epidemiological addictionology studies corroborate the lack of any significant addictive potential of the gabapentinoids, and these drugs are increasingly being used in the treatment of addiction to other substances, with excellent results and no evidence of cross-addiction. However, among individuals with other substance use disorders and, in particular opioid use disorder, there are consistent data showing misuse of gabapentinoids in up to 20% of this population. Although there are allegations of using gabapentinoids to amplify the hedonic effects of opioids, the vast majority of misuse events appear to occur in an attempt to ameliorate opioid withdrawal symptoms. Furthermore, rare but potentially serious respiratory depression may occur, again amplified in the context of opioid or other sedative use. Careful risk:benefit assessment and stratification are warranted when prescription of a gabapentinoid is under consideration, in particular among individuals using opioids. Conclusions Gabapentinoids remain a vital tool in the pain physician’s multimodal armamentarium, but these drugs may not be effective in every clinical situation. Individuals with central sensitization and pain associated with slow-wave sleep deficits and potentially persons with comorbid addictions may benefit the most. The gabapentinoids appear to possess no addictive potential on their own, based on laboratory and clinical data, but they may be abused by persons with opioid use disorders; consequently, cautious risk stratification must take place.

Abstract Occipital neuralgia (ON) is unilateral or bilateral neuralgia in the dermatomal nerve distribution of the greater, lesser or third occipital nerves and is a very common presentation of neuropathic pain. ON, although common and well defined, is still a poorly understood pain syndrome. It often requires invasive treatment for long term and significant pain alleviation; however, the evidence supporting different options is still limited. Several minimally invasive techniques have proven to be efficacious and safe, and the selection depends mostly on response to nerve blocks, patient choice and provider preference. This is a comprehensive review of the latest and seminal literature available about occipital neuralgia and currently available minimally invasive treatment options. It covers the anatomical and physiologic biology at the base of neuralgia, the presentation and diagnostic process. It then reviews the available literature to provide description and comparison of the available methods for alleviation.

Abstract The treatment of noncancer pain in the United States and globally is met with significant challenges, resulting in profound physical, emotional, and societal costs. Based on this need, numerous modalities have been proposed to manage chronic pain, including opioid and nonopioid interventions as well as surgical approaches. Thus, the future of pain management continues to be mired in evolving concepts and constant debates. Consequently, it is crucial to understand the past as we move towards the future. The evolution of lessons for better pain management at present and for the future starting from the 1990s to the present date are reviewed and emphasized with a focus on learning from the past for the future. This review summarizes the evolution of multiple modalities of treatments, including multidisciplinary programs, multimodal therapy, interventional techniques, opioid therapy, other conservative modalities, and surgical interventions. This review emphasizes the individual, patient-centered development of an effective pain treatment plan after proper evaluation to establish a diagnosis. It includes measurable outcomes that focus on improvements in the quality of life and activities of daily living, as well as improvement in pain and function and, most importantly, return to productive citizenship. It is crucial that the knowledge of best practices be advanced, along with emphasis on lessons learned in the past to provide best practices for better pain management.

Abstract Migraine headache is a common, chronic, debilitating disease with a complex etiology. Current therapy for migraine headache comprises either treatments targeting acute migraine pain or prophylactic therapy aimed at increasing the length of time between migraine episodes. Recent evidence suggests that calcium gene-related peptide (CGRP) is a critical component in the pathogenesis of migraines. Fremanezumab, a monoclonal antibody against CGRP, was recently approved by the Food and Drug Administration (FDA) after multiple studies showed that it was well-tolerated, safe, and effective in the treatment of migraines. Further research is needed to elucidate the long-term effects of fremanezumab and CGRP-antagonists in general, and additional data is required in less healthy patients to estimate its effects in these populations and potentially increase the eligible group of recipients. This is a comprehensive review of the current literature on the efficacy and safety of fremanezumab for the treatment of chronic migraine. In this review we provide an update on the epidemiology, pathogenesis, diagnosis, and current treatment of migraine, and summarize the evidence for fremanezumab as a treatment for migraine.

Abstract Purpose of Review This is a comprehensive literature review of the available evidence and techniques of foot injections for chronic pain conditions. It briefly describes common foot chronic pain syndromes and then reviews available injection techniques for each of these syndromes, weighing the available evidence and comparing the available approaches. Recent Findings Foot and ankle pain affects 20% of the population over 50 and significantly impairs mobility and ability to participate in activities of daily living (ADLs), as well as increases fall risk. It is commonly treated with costly surgery, at times with questionable efficacy. Injection therapy is challenging when the etiology is anatomical or compressive. Morton’s neuroma is a budging of the interdigital nerve. Steroid, alcohol, and capsaicin injections provide some benefit, but it is short lived. Hyaluronic acid (HA) injection provided long-term relief and could prove to be a viable treatment option. Achilles tendinopathy (AT) is most likely secondary to repeat tendon stress—platelet-rich-plasma (PRP) and prolotherapy have been trialed for this condition, but more evidence is required to show efficacy. Similar injections were trials for plantar fasciitis and achieved only short-term relief; however, some evidence suggests that PRP injections reduce the frequency of required therapy. Tarsal tunnel syndrome, a compressive neuropathy carries a risk of permanent neural injury if left untreated. Injection therapy can provide a bridge to surgery; however, surgical decompression remains the definitive therapy. When the etiology is inflammatory, steroid injection is more likely to provide benefit. This has been shown in several studies for gout, as well as osteoarthritis of the foot and ankle and treatment-refractory rheumatoid arthritis. HA showed similar benefit, possibly due to anti-inflammatory effects. Stem cell injections may provide the additional benefit of structure restoration. Summary Chronic foot pain is common in the general population and has significant associated morbidity and disability. Traditionally treated with surgery, these are costly and only somewhat effective. Injections provide an effective alternative financially and some evidence exists that they are effective in pain alleviation. However, current evidence is limited and the benefit described from injection therapy has been short-lived in most cases. Further studies in larger populations are required to evaluate the long-term effects of these treatments.

Abstract Introduction This compilation presents a comprehensive review of the literature on common chronic pain conditions of the hand. It briefly presents these common conditions with their biological background, diagnosis, and common management options. It then presents and compares the latest literature available for injection techniques to treat these diagnoses and compares the available evidence. Methods A comprehensive literature review was performed in MEDLINE, PubMed, and Cochrane databases from 1996 to 2019 using the terms “hand pain”, “injection techniques”, “steroid injection”, “chronic pain”, “osteoarthritis”, “rheumatoid arthritis”, “carpal tunnel syndrome”, “De Quervain’s tenosynovitis”, “ganglion cyst”, “gout”, “Raynaud’s”, and “stenosing tenosynovitis”. Results Hand pain is a common condition with 9.7% prevalence in men and 21.6% in women and can cause significant morbidity and disability. It also carries a significant cost to the individuals and the healthcare system, totaling in $4 billion dollars in 2003. Injection therapy is an alternative when conservative treatment fails. Osteoarthritis is the most common chronic hand pain syndrome and affects about 16% of the population. Its mechanism is largely mechanic, and as such, there is controversy if steroid injections are of benefit. Hyaluronic acid (HA) appears to provide substantial relief of pain and may increase functionality. More studies of HA are required to make a definite judgment on its efficacy. Similarly, steroid ganglion cyst injection may confer little benefit. Carpal tunnel syndrome is a compressive neuropathy, and only temporarily relieved with injection therapy. US-guidance provides significant improvement and, while severe cases may still require surgery, can provide a valuable bridge therapy to surgery when conservative treatment fails. Similar bridging treatments and increased efficacy under US-guidance are effective for stenosing tenosynovitis (“trigger finger”), though, interestingly, inflammatory background is associated with decreased effect in this case. When the etiology of the pain is inflammatory, such as in RA, corticosteroid (CS) injections provide significant pain relief and increased functionality. They do not, however, change the course of disease (unlike DMARDs). Another such example is De-Quervain tenosynovitis that sees good benefit from CS injections, and an increased efficacy with US-guidance, and similarly are CS injections for gout. For Raynaud’s phenomenon, Botox injections have encouraging results, but more studies are needed to determine safety and efficacy, as well as the possible difference in effect between primary and secondary Raynaud’s. Conclusions Chronic hand pain is a prevalent and serious condition and can cause significant morbidity and disability and interferes with independence and activities of daily living. Conservative treatment remains the first line of treatment; however, when first-line treatments fail, steroid injections can usually provide benefit. In some cases, HA or Botox may also be beneficial. US-guidance is increasing in hand injection and almost ubiquitously provides safer, more effective injections. Hand surgery remains the alternative for refractory pain.

Abstract Kratom, or Mitragyna, is a tropical plant indigenous to Southeast Asia, with unique pharmacological properties. It is commonly consumed by preparing the leaves into decoction or tea, or by grinding them into a powder. Recent evidence has revealed that kratom has physiological effects similar to opioids, including pain relief and euphoria, as well as stimulant properties, which together raise potential concern for dependence and addiction. Moreover, growing evidence suggests that the prevalence of kratom use is increasing in many parts of the world, raising important considerations for healthcare providers. This manuscript will discuss the most current epidemiology, pharmacology, toxicity, and management related to kratom, while seeking to provide a contemporary perspective on the issue and its role in the greater context of the opioid epidemic.

Abstract Introduction Cosmetic breast surgery is commonly performed in the United States; 520,000 procedures of the total 1.8 million cosmetic surgical procedures performed in 2018 were breast related. Postoperative chronic pain, defined as lasting 3 or more months, has been reported in a wide variety of breast surgical procedures including breast augmentation, reduction mammaplasty, mastectomy, and mastectomy with reconstruction. Patient characteristics associated with the development of postoperative chronic pain following cosmetic breast surgery include a younger age, larger BMI, smaller height, postoperative hyperesthesia, and elevated baseline depression, anxiety, and catastrophizing scores. The anatomical distribution of chronic pain following breast augmentation procedures is dependent upon incision site placement; pectoral and intercostal nerves have been implicated. The purpose of this review is to provide an update on the current literature addressing the pathophysiology, clinical presentation, and treatment of patients presenting with chronic postoperative pain following cosmetic breast surgery. Methods A comprehensive literature review was performed in MEDLINE, PubMed, and Cochrane databases from 1996 to 2019 using the terms “cosmetic surgery”, “breast surgery”, “postoperative pain”, and “chronic pain”. Results Cosmetic breast surgery can have a similar presentation as post-mastectomy pain syndrome and thus have overlapping diagnostic criteria. Seven domains are identified for a diagnosis of PBSPS: Pain after breast surgery, neuropathic in nature, at least a moderate intensity of pain, as defined as within the middle one-third of the selected pain scale, pain for at least 6 months, symptoms occurring for 12 or more hours a day for a minimum of 4 days each week, pain in at least one of the following sites: breast, chest wall, axilla, or arm on the affected side, pain exacerbated by movement. Patient risk factors and surgical risk factors may influence the development of chronic post-cosmetic surgery breast pain. Improved perioperative analgesia including preoperative regional nerve anesthesia and postoperative catheter infusion have been shown to improve chronic postoperative pain outcomes. Conclusions The present review provides a discussion of clinical presentation, pathophysiology, and treatment and preventative strategies for chronic breast pain following cosmetic surgery. This review provides evidence from multiple randomized controlled trials (RCTs) and systematic reviews of efficacy and effectiveness. While chronic postoperative breast pain remains challenging to treat, various preventative strategies have been described to improve postoperative pain outcomes.

Coronavirus disease 2019 (COVID-19) rapidly emerged as a global pandemic, placing imminent stress and burden on healthcare resources and workers worldwide. Many patients who present with a severe COVID-19 infection are at high risk of developing severe acute respiratory distress syndrome (ARDS), leading to a vast number of patients requiring mechanical ventilation and a high mortality rate. Similar to Middle East respiratory syndrome, COVID-19 demonstrates an initial viral replication phase that manifests as a variety of symptoms typically flu-like in nature, followed by a profound inflammatory response leading to rapid production of cytokines and uncontrolled inflammation. There have also been many cases of COVID-19 in pediatric patients presenting with elevated inflammatory markers and multisystem involvement labeled as a multisystem inflammatory syndrome (MIS-C) by the world health organization (WHO). The recent treatment of systemic inflammatory response to COVID-19 targets the secondary phase involving cytokine release syndrome. The detrimental effects of IL-6 can be profound and elevated levels are associated with a higher mortality rate and mechanical ventilation. Tocilizumab is an IL-6 inhibitor most widely investigated to target cytokine storm syndrome. Since June 2021, the FDA enacted an emergency use authorization for tocilizumab in the treatment of COVID-19. Several clinical trials have investigated tocilizumab combined with corticosteroids for treating severe ARDS associated with COVID-19. An increasing amount of evidence suggests that targeting the cytokine storm syndrome related to COVID-19 can lead to improved outcomes, especially in those patients requiring mechanical ventilation and with a critical illness. Additional studies are warranted to further look at the positive effects of tocilizumab in the COVID-19 population while additionally defining possible adverse effects.

Attention deficit hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder in children. Over the past twenty years, research on the disease and its characteristics and treatment options has grown exponentially. The first-line pharmacologic treatment of ADHD is stimulants, which have a response rate of ~70%. With the support of four phase 3 studies involving more than 1,000 pediatric patients 6–17 years old, the FDA has approved the non-stimulant, serotonin-norepinephrine modulating agent (SNMA) viloxazine in an extended-release capsule (viloxazine ER) for treatment of ADHD in children aged 6–17. Viloxazine modulates serotonergic activity as a selective 5-HT22B receptor antagonist and 5-HT2C receptor agonist and moderately inhibits norepinephrine transporter (NET), thus blocking the reuptake of norepinephrine. A phase 2 study by Johnson et al. found that once-daily dosing of viloxazine ER in 200, 300, or 400 mg dosages in children with ADHD for eight weeks resulted in a statistically significant reduction of ADHD-RS-IV total score. A post hoc analysis of data from four phase 3, randomized, placebo-controlled, double-blind, three-arm, clinical trials by Faraone et al. found that early response to viloxazine treatment, defined as a change in ADHD-RS-5 total score at week 2, best predicted the treatment response at week 6 [75% positive predictive power (PPP), 75% sensitivity]. Proper treatment of the symptoms and comorbidities associated with ADHD is crucial in improving a patient's quality of life, cognitive function, and overall therapeutic outcomes. Viloxazine's mechanism of action, clinical effects, and limited side effect profile point toward the drug's relevance in the treatment of ADHD.

Regional anesthesia is an important aspect of the overall anesthetic plan for patients. It has the potential to offer superior benefits compared to opioid-based treatment and is an important component of Enhanced Recovery after Surgery (ERAS) protocols. The use of the pectoral type I (PECS I) and pectoral type II blocks (PECS II) has been shown to reduce postoperative pain and opioid consumption in patients undergoing complete mastectomy and breast surgery. We describe the use of dexamethasone and dexmedetomidine to prolong the analgesic effects of these regional blocks in a patient undergoing total mastectomy with lymph node dissection.

Background: When prescribing antibiotics, infection eradication rates, local resistance rates, and cost should be among the most essential considerations. Helicobacter pylori is among the most common infections worldwide, and it can lead to burdensome sequela for the patient and the healthcare system, without appropriate treatment. Due to constantly fluctuating resistance rates, regimens must be constantly assessed to ensure effectiveness. Methods: This was a narrative review. The sources for this review are as follows: searching on PubMed, Google Scholar, Medline, and ScienceDirect; using keywords: Helicobacter pylori, Treatment Options, Clinical Practice. Results: Multiple antibiotics are prescribed as part of the regimen to thwart high resistance rates. This can lead to unwanted adverse reactions and adherence issues, due to the amount and timing of medication administration, which also may contribute to resistance. Single-capsule combination capsules have reached the market to ease this concern, but brand-only may be problematic for patient affordability. Due to the previously mentioned factors, effectiveness and affordability must be equally considered. Conclusions: This review will utilize guidelines to discuss current treatment options and give cost considerations to elicit the most effective regimen for the patient.

Postpartum depression (PPD) is one of the three major categories on the spectrum of postpartum psychiatric syndromes. Postpartum psychiatric syndromes are classified as either postpartum blues, postpartum depression, or postpartum psychosis. Postpartum depression is important to recognize clinically because of the effect it can have on the mother-child bond. The neurosteroid allopregnanolone, a progesterone derivative, is important for its role in positively modulating GABAA receptors. GABA-mediated signaling has been previously implicated in major depressive disorder. Allopregnanolone-mediated signaling has been identified as an important therapeutic target. Treatment with an allopregnanolone-analog, brexanolone, has been shown to improve depression scores in trials for the treatment of PPD. Brexanolone is a positive allosteric modulator of GABAA and is the first drug approved by the FDA to treat postpartum depression. Brexanolone enhances the inhibitory effects of GABAA, restores dysfunctional GABAA transmembrane channels, and mimics a naturally produced progesterone metabolite that fluctuates during pregnancy and postpartum. One open-label study and two phase two studies have some significant reduction in HAM-D scores after treatment and that the effect was still there 30 days post-treatment. Per the data reported, intravenous infusion of brexanolone could be efficacious and safe for the treatment of women suffering from postpartum depression.

Given the typical age onset of schizophrenia, there are tremendous economic and social impacts that extend beyond the person and their families. One critical determinant of the diseases' impact is the patient's adherence to antipsychotic drug treatment. Approved in 2015 for the treatment of schizophrenia, paliperidone palmitate (Invega Trinza, a 3-month injection, noted as PP3M) is a second-generation long-acting injectable antipsychotic medication. Among the different formulations offered for palmitate paliperidone, including the 1 and 3-month formulations, the longer duration 3-month formulation was better at preventing relapse in schizophrenic patients. To date, different formulations of palmitate paliperidone that have been studied on relapse episodes of schizophrenia include once-daily extended-release oral paliperidone (ORAL paliperidone), once-monthly paliperidone palmitate (PP1M), and once-every-3-months paliperidone palmitate (PP3M). Post-hoc analyses show that patients who were withdrawn from PP1M paliperidone had the least risk of relapse, followed by patients withdrawn from PP3M and patients withdrawn from ORAL paliperidone. PP3M was better at preventing relapse compared to ORAL paliperidone. The results demonstrated that 50% of patients who were withdrawn from ORAL paliperidone, PP1M, or PP3M remained relapse-free for ~2, 6, and 13 months, respectively. Compared to PP1M, PP3M is just as safe and effective and has the added advantage of increased adherence related to a longer dose interval, decreasing the risk of relapse.

With the ongoing public health crisis with prescription opioids, there is a need for safer alternatives for medication management in chronic pain patients. Buprenorphine is a partial mu-opioid agonist which is commonly utilized to treat patients with opioid-use disorders. The purpose of this review is to discuss the potential use of this medication for the treatment of chronic pain instead of resorting to more traditional Schedule II opioids. Buprenorphine offers a safer alternative for patients who require opioids to manage chronic pain, given the unique pharmacological properties that allow it to provide adequate analgesia with less abuse potential.

# Purpose of review This is a comprehensive review of the literature regarding the use of milnacipran in treating fibromyalgia. A chronic pain disorder with other system disturbances, fibromyalgia is often resistant to many therapeutic approaches. This review presents the background, evidence, and indications for using milnacipran as a treatment option for this condition. # Recent Findings The definition of fibromyalgia has evolved over many years as it is a relatively tricky syndrome to measure objectively. Today, it is characterized by chronic, widespread pain accompanied by alterations in sleep, mood, and other behavioral aspects. A variety of therapeutic regimens currently used to treat the syndrome as a singular approach are rarely effective. Milnacipran is one of three drugs currently approved by the FDA for the treatment of fibromyalgia. It acts as a serotonin and norepinephrine reuptake inhibitor, which results in decreased pain transmission. Milnacipran remains an effective treatment option for fibromyalgia in adults and needs to be further evaluated with existing therapeutic approaches. # Summary Fibromyalgia is a broad-spectrum disorder primarily characterized by chronic pain coupled with disturbances in cognitive functioning and sleep. The progression of this syndrome is often debilitating and significantly affects the quality of life. Milnacipran is one of three FDA-approved drugs used to alleviate the symptom burden and is comparatively more therapeutic in specific domains of fibromyalgia. A more holistic approach is needed to treat fibromyalgia effectively and further research, including direct comparison studies, should be conducted to fully evaluate the usefulness of this drug.

# Background Chronic pain significantly worsens the quality of life. Unlike neuropathic, musculoskeletal, postoperative pain, and cancer pain, chronic primary pain cannot be explained by an underlying disease or condition, making its treatment arduous. # Objectives This manuscript intends to provide a comprehensive review of the use of ketamine as a treatment option for specific chronic pain conditions. # Study Design A review article. # Setting A review of the literature. # Methods A search was done on PubMed for relevant articles. # Results A comprehensive review of the current understanding of chronic pain and the treatment of specific chronic pain conditions with ketamine. # Limitations Literature is scarce regarding the use of ketamine for the treatment of chronic pain. # Conclusion First-line treatment for many chronic pain conditions includes NSAIDs, antidepressants, anticonvulsants, and opioids. However, these treatment methods are unsuccessful in a subset of patients. Ketamine has been explored in randomized controlled trials (RCTs) as an alternative treatment option, and it has been demonstrated to improve pain symptoms, patient satisfaction, and quality of life. Conditions highlighted in this review include neuropathic pain, fibromyalgia, complex regional pain syndrome (CRPS), phantom limb pain (PLP), cancer pain, and post-thoracotomy pain syndrome. This review will discuss conditions, such as neuropathic pain, fibromyalgia, complex regional pain syndrome, and more and ketamine’s efficacy and its supplementary benefits in the chronic pain patient population. As the opioid crisis in the United States continues to persist, this review aims to understand better multimodal analgesia, which can improve how chronic pain is managed.

Abstract Introduction Total knee arthroplasty (TKA) is an effective treatment modality for severe osteoarthritis of the knee. Causes of pain following TKA are poorly understood; however, patient-specific biology and various neuropathic underlying mechanisms such as neuroma formation and complex regional pain syndrome (CRPS) have been suggested. Our case demonstrated the successful treatment of CRPS in the knee with the use of combination therapy in spinal cord stimulator. Case We present a 71-year-old Caucasian non-Hispanic male who presented with chronic left knee pain after undergoing a total knee arthroplasty (TKA) 18 months prior. Following his TKA, he reported doing well in the acute post-operative period but began to develop progressively worsening left knee pain at approximately the third post-operative week. He underwent a successful spinal cord stimulator (SCS) trial and subsequent implantation of two 16-contact Boston Scientific leads with a Boston Scientific Spectra WaveWriterTM SCS system. Upon first post-procedural follow-up, and moreover at his 6-month follow-up, the patient reported complete resolution of his symptoms. Discussion The development of persistent pain following TKA is a significant complication that is often challenging to treat. Our case demonstrated the successful treatment of CRPS in the knee with the use of combination therapy in spinal cord stimulator therapy. We anticipate that more data will continue to emerge to assess for the safety and efficacy of combination therapy.

Abstract Thoracic outlet syndrome, a group of diverse disorders, is a collection of symptoms in the shoulder and upper extremity area that results in pain, numbness, and tingling. Identification of thoracic outlet syndrome is complex and a thorough clinical examination in addition to appropriate clinical testing can aide in diagnosis. Practitioners must consider the pathology of thoracic outlet syndrome in their differential diagnosis for shoulder and upper extremity pain symptoms so that patients are directed appropriately to timely therapeutic interventions. Patients with a definitive etiology who have failed conservative management are ideal candidates for surgical correction. This manuscript will discuss thoracic outlet syndrome, occurrence, physical presentation, clinical implications, diagnosis, and management.

Enhanced recovery pathways are a novel approach focused on enhancing the care of surgical patients. “Prehabilitation” is the term applied to any intervention administered before surgery to reduce surgery-related morbidity, decrease the length of hospital stay, expedite the return of organ function, and facilitate the patient's return to normal life. A PubMed search was performed with the following key words: enhanced recovery, preoperative preparation, cessation of smoking and euvolemia. The results from this Pubmed search revealed that female patients may have higher levels of anxiety than male patients. Intensive smoking and alcohol cessation 6–8 weeks before elective surgery may reduce the incidence of postoperative morbidity. Preoperative exercise can be effective for reducing the postoperative complications like pulmonary complications and shortening the length of hospital stay. It is safe to allow patients to drink clear fluids up until 2 h before elective surgery (Level II evidence). Perioperative normoglycemia is the single most important factor to prevent surgical site infection. Intermittent pneumatic compression devices and low molecular weight heparin are effective in preventing postoperative thromboembolism. No advantage is gained by preoperative mechanical bowel preparation in elective colorectal surgery. The goal of preoperative fluid management is for the patient to arrive in the operating room in a hydrated and euvolemic state. Mild perioperative hypothermia may promote surgical wound infection by triggering thermoregulatory vasoconstriction, which decreases subcutaneous oxygen tension.

# Purpose of Review This is a comprehensive review of the literature regarding the use of Lumateperone tosylate for schizophrenia. This review presents the background, evidence, and indications for the use of lumateperone tosylate in the treatment of schizophrenia. # Recent Findings Schizophrenia is a chronic mental health disorder that affects approximately 3.3 million people in the United States. Its symptoms, which must be present more than six months, are comprised of disorganized behavior and speech, a diminished capacity to comprehend reality, hearing voices unheard by others, seeing things unseen by others, delusions, decreased social commitment, and decreased motivation. The majority of these symptoms can be managed with antipsychotic medication. Lumateperone is a selective and concurrent modulator of serotonin, dopamine, and glutamate, which all mediate or modulate serious mental illness. # Summary Schizophrenia is a complex, severe mental illness that affects how the brain processes information. There are many medications used to treat schizophrenia. One antipsychotic agent, lumateperone tosylate, is a newer agent that the FDA recently approved. The most common adverse effects are shown to be mild such as somnolence, constipation, sedation, and fatigue, with the 42 mg recommended dose. Lumateperone tosylate is an FDA-approved drug that can be given only at the 42mg dose once daily with no titration requirements.

# Purpose of review This a comprehensive review of the literature regarding the use of Valbenazine in treating tardive dyskinesia. A primarily oral movement disorder induced by chronic exposure to certain classes of medications, tardive dyskinesia is often resistant to many therapeutic approaches. This review presents the background, evidence, and indications for the use of Valbenazine as a treatment option for this condition. # Recent Findings Tardive dyskinesia is a disorder arising from long-term exposure to medications that blocked dopamine receptors, primarily antipsychotics. It is characterized by abnormal movements of the oral-buccal-lingual structures as well as associated pain and hypertrophy. Simply stopping the use of the dopamine blocking agents effectively alleviates the symptoms but is not always reliable hence the need for another therapeutic approach. Valbenazine is thought to function as a highly selective inhibitor of the VMAT2 vesicular monoamine transporter resulting in decreased availability of dopamine in the presynaptic cleft. This leads to decreased dopaminergic activation of the striatal motor pathway. The FDA approved Valbenazine in 2017 to treat tardive dyskinesia in adults and needs to be evaluated with existing therapeutic approaches. # Summary The chronic use of dopamine receptor blocking agents, most commonly antipsychotics, can lead to a movement disorder called tardive dyskinesia. Once symptom onset has occurred, these movement abnormalities can persist for years to permanently, depending on the speed and effectiveness of treatment. Valbenazine is a relatively newer option for the treatment of tardive dyskinesia in adults. Compared to other pharmaceutical agents, it is more selective and has limited toxicities making it an effective treatment regimen. However, further research, including additional direct comparison studies, should be conducted to fully evaluate this drug’s usefulness.

# Purpose of Review Insomnia is a common type of sleep disorder defined by an ongoing difficulty initiating or maintaining sleep or nonrestorative sleep with subsequent daytime impairment. The sleep disturbances in insomnia usually manifest as difficulty in falling asleep, maintaining the continuity of sleep, or waking up too early in the morning well before the desired time, irrespective of the adequate circumstances to sleep every night. Insomnia can significantly impact daytime functioning resulting in decreased workplace productivity, proneness to errors and accidents, inability to concentrate, frequent daytime naps, and poor quality of life. The treatment of insomnia should involve a multi-disciplinary approach, focusing on implementing behavioral interventions, improving sleep hygiene, managing psychological stressors, hypnotic treatment, and pharmacological therapy. The most effective therapies utilize cognitive behavioral therapy in conjunction with pharmacotherapy to minimize the needed dose and any resulting side effects. Non-benzodiazepine hypnotics such as zolpidem, eszopiclone, zaleplon are the most used as adjunctive treatment. One of the most used of these hypnotics is zolpidem. However, zolpidem has a wide variety of adverse effects and has some special considerations noted in the literature. # Recent Findings Zolpidem has been associated with an increased risk of falls in hospitalized patients with an OR of 4.28 (P \

# Purpose of review This is a comprehensive review of the literature regarding the use of ketamine as a treatment for treatment-resistant depression (TRD). It covers the epidemiology, risk factors, pathophysiology, and current treatment modalities regarding Major Depressive Disorder (MDD) and TRD. It provides background on the mechanism of action of ketamine, its history, current approved and off-label indications in the field of psychiatry, and then provides an overview of the existing evidence for the use of ketamine in the treatment of TRD. # Recent findings MDD is a mental illness that puts an enormous strain on the affected and a high socio-economic burden on society. The illness is complex and combines genetic, pathophysiologic, and environmental factors that combine to negatively affect neurotransmitter balance in the brain. Additional evidence suggests dysregulation of the hypothalamic-pituitary (HPA) axis, brain-derived neurotrophic factor (BDNF), vitamin D levels, and involvement of pro-inflammatory markers. Core symptoms include depressed mood or anhedonia, combined with neurovegetative symptoms such as sleep impairment, changes in appetite, feelings of worthlessness and guilt, and psychomotor retardation. Current first-line treatment options are antidepressants of the selective serotonin reuptake inhibitor (SSRI) and serotonin-norepinephrine reuptake inhibitor (SNRI) class. Failure to respond to two adequate trials of treatment meets the criteria for TRD. Esketamine (Spravato) is an NMDA-receptor antagonist with additional AMPA-receptor agonist properties, which the FDA approved in 2019 to treat adult TRD in conjunction with an oral antidepressant. It can be administered intranasally, providing a rapid response and proven effective and safe. Additional research suggests that oral ketamine might be effective for PTSD and anxiety disorders. Intravenous administration of ketamine has also shown benefits for acute suicidal ideation and depression and substance use to reduce relapse rates. # Summary TRD is associated with huge costs on individual and societal levels. Underlying disease processes are multifactorial and not well understood. Adjunctive therapies for TRD with proven benefits exist, but acutely depressed and suicidal patients often require prolonged inpatient stabilization. Intranasal esketamine is a new FDA-approved alternative with rapid benefit for TRD, which has also shown a rapid reduction in suicidal ideation while maintaining a favorable side-effect profile. Additional potential off-label uses for ketamine in psychiatric disorders have been studied, including PTSD, anxiety disorders, bipolar depression, and substance use disorders.

# Introduction Fibromyalgia (FM) is a complex disorder characterized primarily by chronic, widespread musculoskeletal pain. Currently, the Food and Drug Administration (FDA) has approved the use of three medications to treat FM: pregabalin, duloxetine, and milnacipran. The pharmaceutical intervention has lacked consistent pain relief among all patients. Therefore, the investigation into alternative treatment options has grown in interest. This narrative review aims to evaluate the evidence regarding vitamin D for the treatment of FM. # Methods Narrative review. # Results Low serum vitamin D has been linked to various chronic pain states. An association between vitamin D deficiency and FM has been reported but is controversial in the literature. Some studies have documented the beneficial effects of vitamin D supplementation on reducing pain symptoms and improving the overall quality of life in those with FM. Despite these positive findings, many of the studies regarding this topic lack adequate power to make substantial conclusions about the effects of vitamin D on FM. # Conclusion Existing studies provide promising results. However, additional high-quality data on vitamin D supplementation is needed before recommendations for pain management can be made. Vitamin D supplementation is inexpensive, has minimal side effects, and can benefit FM patients regardless of its efficacy in pain control. Additionally, high-quality studies are warranted to fully elucidate the potential of vitamin D to manage chronic pain in FM.

Benzodiazepines are one of the most commonly used medications in the field of anesthesia. They offer excellent anxiolytic and amnestic properties ideal for the perioperative period when patient anxiety is understandably heightened. Remimazolam has presented a favorable alternative to some of the common intravenous anesthetic agents used given its fast onset of action, high safety profile, and reasonably short duration of action. The drugs within the four classes of benzodiazepines, 2-keto-benzodiazepines, 3-hydroxy-benzodiazepines, triazolo-benzodiazepines, and 7-nitro-benzodiazepines provide varying degrees of anxiolysis, sedation, and amnesia. This is provided by the benzodiazepine molecule binding and causing a conformational change to the chloride ion channel to cause hyperpolarization and thus inhibition of the central nervous system. Each type of benzodiazepine has a preferred role within the realm of medicine. For instance, diazepam is used for the treatment of seizures and anxiety. Midazolam’s anxiolytic and anterograde amnestic properties are taking advantage of during the perioperative period. Lorazepam is beneficial for anxiety and status epilepticus. Remimazolam, currently in phase II and III clinical trials, has demonstrated a very short during of action and low context-sensitive half-time, allowing for its rapid removal even during a prolonged infusion. Much of its properties may be credited to being a soft drug, meaning it is a metabolically active drug that is rapidly inactivated in the body. This provides anesthesiologists and other practitioners administering it with a more predictable sedative. These properties have the potential to push it towards becoming the drug of choice for premedication during the perioperative period and sedation in the ICU. Furthermore, remimazolam does not seem to rely on any specific organ to be metabolized. The drug's ester moiety makes it a substrate for non-specific tissue esterase enzymes, meaning its metabolism and elimination are not impaired in patients with hepatic and/or renal disease. Its addictive potential closely resembles that of its parent compound, midazolam. Reports of its adverse reactions include headache and somnolence after an involuntary movement during infusion. Benzodiazepines are a great adjunct to anesthetic care. Remimazolam’s safety profile, pharmacokinetics, pharmacodynamics, and potential practical use make it quite favorable in this regard. It has the potential to equip anesthesiologists and other medical practitioners with a more predictable medication that has a good safety profile. However, further large clinical trials will provide us with a better understanding of the advantages and disadvantages of remimazolam.

Opiates are routinely used for chronic pain patients, and up to 44% of them will have a prescription for an opiate medication for pain alleviation. However, of the 76 million adults prescribed opiates for pain management, about 12% report misuse, and a large number of these may find themselves addicted to opioid medications. Opioid addiction is an ongoing epidemic, costing many lives. Withdrawal is very difficult. This requires providers to consider alternative analgesic plans and minimize opiate use. Here we report the use of a dexamethasone-dexmedetomidine combination for a regional nerve block in an elderly woman chronically treated with opiate medications who had previously failed opiate weaning. Following her nerve block, she was able to completely wean off of opioids and continues having good pain control with an opioid-free regimen.

Spinal cord stimulation is an effective treatment modality for patients with numerous pain conditions. Although proven to be highly successful, device implantation does come with some inherent risks. One of the most challenging complications is perioperative infection. For most patients, a simple trial of oral antibiotics and in-office drainage of any superficial infectious material may be sufficient. Deeper infections with wound dehiscence necessitate device removal and intravenous antibiotic therapy. The question remains, if the device was previously providing pain relief for the patient, when is the appropriate time to reimplant the device after the infection has cleared? We describe the case of explantation of an infected device and successful reimplantation after 1 year.